Methods for Treating Conditions Such as Dystonia and Post-Stroke Spasticity with Clonidine

ABSTRACT

Effective treatments of dystonia and/or post-stroke spasticity for extended periods of time are provided. Through the administration of an effective amount of clonidine at or near a target site, one can relieve dystonia and/or post-stroke spasticity caused by diverse sources. When appropriate formulations are provided within biodegradable polymers, this relief can be continued for at least five days. In some embodiments, the relief can be for at least twenty-five days, at least fifty days, at least one hundred days, at least one hundred and thirty-five days or at least one hundred and eighty days.

This application claims the benefit of the filing date of U.S.Provisional Patent Application No. 61/046,201, filed Apr. 18, 2008 andentitled “Clonidine Formulations In A Biodegradable Polymer Carrier” andU.S. Provisional Patent Application No. 61/046,192, filed Apr. 18, 2008and entitled “Methods for Treating Post-Operative Effects Such asSpasticity and Shivering with Clonidine.” The entire disclosures of bothof these provisional patent applications are hereby incorporated byreference into the present disclosure.

BACKGROUND OF THE INVENTION

Dystonia is a neurologic movement disorder characterized by sustainedmuscle contractions, usually producing twisting and repetitive movementsor abnormal postures or positions. Almost all dystonic movements share adirectional quality that is typically sustained. Movements may beprolonged or occur in an instant. In general, dystonia may be classifiedbased on: the age at which symptoms appear; the area or areas of thebody that are affected (anatomical distribution); or the cause of thedystonia.

Cervical dystonia, the most common form of focal dystonia, ischaracterized by abnormal squeezing and twisting muscle contractions inthe head and neck area. The dystonic muscle spasms associated withcervical dystonia (CD) may affect any combination of neck muscles.Sustained muscle contractions result in abnormal positions or posturingof the head and neck which results in considerable pain and discomfort.Periodic or patterned spasms result in jerky head movements or periodicor sustained unnatural positioning of the head (dystonic posturing).Sideways or lateral rotation of the head and twisting of the neck islikely the most common finding in CD. This is known as rotationalcervical dystonia. In addition, tilting of the head is often present.

Cervical dystonia may begin in the neck and spread into the shoulders,but the symptoms usually plateau and remain stable within five years ofonset. This form of focal dystonia is unlikely to spread beyond the neckand shoulders or become generalized dystonia. Occasionally, people withcervical dystonia develop other focal dystonias.

Cervical dystonia may be primary (meaning that it is the only apparentneurological disorder, with or without a family history) or be broughtabout by secondary causes such as physical trauma. Cases of inheritedcervical dystonia may occur in conjunction with early-onset generalizeddystonia, which is associated with the DYT1 gene.

Muscle hypertrophy is present in almost all CD patients. Over two-thirdsor up to 80% of patients have associated neck pain. About 33% to 40% ofthese patients also experience head tremor (i.e., dystonic tremor), handtremor, or both. Approximately 20% of patients with CD also haveblepharospasm or dystonia in other muscles or in muscle groups of thearm or hand. In addition, about 15% of patients have hand tremorresembling essential tremor.

Medical therapies are available for treating dystonia including cervicaldystonia, but not all patients get adequate relief. DBS is a surgicalprocedure that interrupts neuronal circuits in the globus pallidusinterna (Gpi) and subthalamic nucleus (STN)—areas of the basal gangliaof the brain that do not work correctly in patients with dystonia. Thismay lessen patients' symptoms and pain but results in decreasedmovement. Another treatment is regular botulinum toxin injections to theaffected muscle, however, this can result in weakness in the muscle atthe site of injection, muscle soreness throughout the body, difficultyswallowing, breathing or talking, double vision and/or hoarseness forseveral days. In addition, high and frequent doses of botulinum toxincould be fatal as botulinum toxin is made of the same bacterium thatcauses food poisoning. Also, some oral medications have demonstratedsome benefit including anticholinergic drugs such asArtane®(trihexyphenidyl) and Cogentin® (benztropine); dopaninergic drugssuch as Sinemet® or Madopar® (levodopa), Parlodel® (bromocriptine), andSymmetrel® (amantadine); and GABAergic drugs such as Valium® (diazepam).However, these medications can have undesirable side effects includingcentral nervous system side effects such as confusion, drowsiness,hallucination, personality change and memory difficulties, andperipheral nervous system side effects such as dry mouth, blurredvision, urinary retention and constipation.

Another debilitating condition is post-stroke spasticity. This can occurafter a stroke as certain muscles may start to contract involuntarily.Post-stroke spasticity is characterized by increased muscle tone andresistance to movement. The increased stiffness contributes to fatigueby forcing stroke survivors to expend much more energy to perform basicactivities. Complications of inadequately controlled post-strokespasticity include pain, contractures and decubiti. Up to 30% of strokesurvivors suffer this disabling spasticity. Present medical treatmentsinclude the use of pharmaceuticals such as baclofen, diazepam anddantrolene. However, these medications often cause sedation in patientsor lethargy. Further, some patients experience confusion.

Another treatment for post-stroke spasticity is the use of botulinumtoxin A (“Botox”). However, there are many undesirable side effects thatcan be experienced with the use of Botox as mentioned above. Undesirableside effects of Botox include having trouble breathing, talking, orswallowing; drooping eyelids; unusual or severe muscle weakness(especially in a body area that was not injected with the medication);problems with vision or depth perception; crusting or drainage from youreyes; severe skin rashes or itching; and/or chest pain or a heavyfeeling with pain spreading to the arm or shoulder, a general illfeeling.

A pharmaceutical with minimal side effects that is known to the medicalprofession for treating spasticity due to brain damage is clonidine,which is widely recognized as an antihypertensive agent that acts as anagonist on the alpha-2-adrenergic receptor and a neural receptoragonist. In general, clonidine, also referred to as2,6-dichloro-N-2-imidazolidinyldenebenzenamine (C₉H₉Cl₂N₃), may berepresented by the following chemical structure:

However, to date clonidine has not been widely appreciated as atreatment for conditions such as dystonia and post-stroke spasticity.Thus, there is a need to develop effective formulations of this compoundfor these applications.

SUMMARY OF THE INVENTION

Compositions and methods are provided comprising clonidine or itspharmaceutically acceptable salts that are administered in order totreat or reduce dystonia and/or post-stroke spasticity.

In one exemplary embodiment, an implantable drug depot for reducing,preventing or treating dystonia and/or post-stroke spasticity in apatient in need of such treatment is provided. The drug depot comprisesat least one biodegradeable polymer and clonidine or a pharmaceuticallyacceptable salt thereof in an amount from about 0.1 wt. % to about 30wt. % of the drug depot. The drug depot is capable of releasingclonidine over a period of 5 to 135 days. The clonidine orpharmaceutically acceptable salt thereof can be released at an amountbetween 0.005 and 1.0 mg per day for the period of 5 to 135 days.

In another exemplary embodiment, an implantable drug depot for reducing,preventing or treating dystonia and/or post-stroke spasticity in apatient in need of such treatment is provided, wherein the drug depotcomprises at least one biodegradeable polymer and clonidine or apharmaceutically acceptable salt thereof in an amount from about 0.1 wt.% to about 30 wt. % of the drug depot, and the drug depot releases: (i)a bolus dose of the clonidine; and (ii) an effective amount of theclonidine over a period of at least fifty days.

In another exemplary embodiment, a method for treating dystonia and/orpost-stroke spasticity is provided. The method comprises implanting adrug depot in an organism to reduce, prevent or treat dystonia and/orpost-stroke spasticity, wherein the drug depot comprises clonidine in anamount from about 0.1 wt. % to about 30 wt. % of the drug depot, and atleast one biodegradable polymer. The clonidine is capable of beingreleased in an amount between 0.005 and 1.0 mg per day for a period of 5to 135 days.

In still another exemplary embodiment, another method for treatingdystonia and/or post-stroke spasticity is provided. The method comprisesimplanting a drug depot in an organism to reduce, prevent or treatdystonia and/or post-stroke spasticity. The drug depot comprisesclonidine in an amount from about 0.1 wt. % to about 30 wt. % of thedrug depot, and at least one biodegradable polymer. The drug depot iscapable of releasing about 5% to about 100% of the clonidine relative toa total amount of the clonidine loaded in the drug depot over a periodof 3 to 200 days after the drug depot is implanted in the organism.

In still yet another exemplary embodiment, an implantable drug depotuseful for reducing, preventing or treating dystonia and/or post-strokespasticity in a patient in need of such treatment is provided, whereinthe drug depot comprises at least one biodegradeable polymer and atherapeutically effective amount of clonidine, the drug depot isadministered at a site to reduce, prevent or treat dystonia and/orpost-stroke spasticity, and the drug depot is capable of releasingclonidine at an amount between 0.005 and 1.0 mg per day for a period of5 to 135 days at the site.

In another exemplary embodiment, there is a sustain release compositioncomprising an effective amount of clonidine or a pharmaceuticallyacceptable salt thereof in an implantable drug depot, wherein theclonidine or a pharmaceutically acceptable salt thereof is present in anamount to relieve post-stroke spasticity and/or dystonia for a period of5 to 135 days and wherein the implantable drug depot facilitates sustainrelease of clonidine over the period.

In another exemplary embodiment, a method of making an implantable drugdepot is provided. The method comprises combining a biocompatiblepolymer and a therapeutically effective amount of clonidine orpharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

Clonidine in the various embodiments may be in the form of a salt. Oneexample of a salt is a hydrochloric salt. In various embodiments,clonidine may be in the form of a base. In various embodiments,clonidine may be in the form of a mixture of clonidine base and ahydrochloride salt. Further, clonidine or a pharmaceutically acceptablesalt thereof may be encapsulated in a plurality of depots comprisingmicroparticles, microspheres, microcapsules, and/or microfibers whichcould be suspended in a gel. The drug depot may be a pellet.

Clonidine or a pharmaceutically acceptable salt thereof may be presentin various embodiments in an amount from about 0.1 wt. % to about 30 wt.% of the drug depot. In some embodiments, clonidine may comprise fromabout 5 wt. % to about 15 wt. % of the drug depot.

The polymer in various embodiments of this invention comprises one ormore of poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone, andD,L-lactide-co-glycolide-co-ε-caprolactone. Further, the polymer iscapable of degrading or degrades in 200 days or less after the drugdepot is administered to reduce, prevent or treat dystonia and/orpost-stroke spasticity. Also, the polymer may comprise at least about70% of the total wt. % of the drug depot. In various embodiments, thepolymer may comprise poly(lactic-co-glycolic acid) and thepoly(lactic-co-glycolic acid) comprises a mixture of polyglycolide andpolylactide. The mixture can comprise more polylactide thanpolyglycolide.

The drug depot in various embodiments is capable of releasing between0.005 and 3 milligrams (mg) per day of clonidine or pharmaceuticallyacceptable salt thereof to reduce, prevent or treat dystonia and/orpost-stroke spasticity. In some embodiments, the drug depot is capableof releasing between 0.01 and 0.1 mg per day of clonidine orpharmaceutically acceptable salt thereof to reduce, prevent or treatdystonia and/or post-stroke spasticity.

The drug depot in various embodiments may comprise a radiographic markeradapted to assist in radiographic imaging. The radiographic marker maycomprise barium, bismuth, tungsten, tantalum, iodine, calcium phosphateand/or metal beads.

The drug depot in various embodiments may comprise at least oneadditional anti-inflammatory or analgesic agent, at least one anabolicor an anti-catabolic growth factor or a combination thereof.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a number of common locations within a patient thatmay be sites at which surgery takes place and locations at which thedrug depot containing clonidine can locally be administered thereto andused to treat dystonia and/or post-stroke spasticity.

FIG. 2 illustrates a schematic dorsal view of the spine and sites wherethe drug depot containing clonidine can locally be administered thereto.

FIG. 3 is a graphic representation of the thermal paw withdrawal latencyas a percentage from baseline for the following administrations:clonidine 0.02 mg/kg/day subcutaneously, 100 DL 7E Control, 5% CL-HCL,CL 5%, CL 8%, 1 CL 7%, POE Control and POE CL-Base, at 7 days, 14 days,21 days, 28 days, 35 days, 42 days, 49 days, 56 days and 63 days. CL-HCLrefers to clonidine hydrochloride. “POE” refers to poly(orthoester).“CL-Base” refers to clonidine in its base form.

FIG. 4 is a graphic representation of the mechanical threshold as apercentage from baseline for the following administrations: clonidine0.02 mg/kg/day subcutaneously, 100 DL 7E Control, 5% CL-HCL, CL 5%, CL8%, CL 7%, POE Control and POE CL-Base, at 8 days, 15 days, 22 days, 29days, 36 days, 43 days, 50 days, 57 days and 64 days.

FIG. 5 is a graphic representation of an in vitro release of clonidinefrom three pellet doses as measured by percentage release.

FIG. 6 is a graphic representation of the calculated daily release ofclonidine from three pellet doses as measured by micrograms released invitro.

FIG. 7 is a graphic representation of clonidine HCl release for variousformulations as measured by the cumulative clonidine releasedpercentage.

FIG. 8 is a graphic representation of the cumulative in vitro releaseprofile for certain clonidine formulations.

FIG. 9 is a graphic representation of the cumulative release profilesfor certain irradiated clonidine HCl formulations.

FIG. 10 is a graphic representation of certain calculated daily releasemeasurements of clonidine from 2/3/4 pellets doses.

FIG. 11 is a graphic representation of the calculated daily release ofclonidine from certain three pellet doses.

FIG. 12 is a graphic representation of the cumulative in vitro releaseprofile of clonidine from certain coaxial formulations.

FIG. 13 is a graphic representation of the cumulative in vitro releaseprofile for certain irradiated clonidine formulations.

FIG. 14 is a graphic representation of the calculated daily release ofclonidine for certain three pellet dose formulations.

FIG. 15 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 16 is a graphic representation of the micrograms of clonidinereleased for certain 3/4/5 pellet dose formulations.

FIG. 17 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 18 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 19 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 20 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 21 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 22 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 23 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 24 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 25 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 26 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 27 is a graphic representation of the cumulative elution percentageof clonidine for one formulation.

FIG. 28 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 29 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 30 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 31 is a graphic representation of the cumulative elution percentageof clonidine for one formulation.

FIG. 32 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 33 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 34 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

A “drug depot” is the composition in which the clonidine is administeredto the body. Thus, a drug depot may comprise a physical structure tofacilitate implantation and retention in a desired site. The drug depotmay also comprise the drug itself. The term “drug” as used herein isgenerally meant to refer to any substance that alters the physiology ofa patient. The term “drug” may be used interchangeably herein with theterms “therapeutic agent,” “therapeutically effective amount” and“active pharmaceutical ingredient” or “API.” It will be understood thatunless otherwise specified a “drug” formulation may include more thanone therapeutic agent, wherein exemplary combinations of therapeuticagents include a combination of two or more drugs. The drug provides aconcentration gradient of the therapeutic agent for delivery to thesite. In various embodiments, the drug depot provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 0.01 cm to about 5 cm from the administration site and comprisesclonidine. A drug depot may also include a pump or pellet.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition, reduction or alleviation ofdystonia and/or post-stroke spasticity, improvement in the conditionthrough muscle relaxation, etc. The dosage administered to a patient canbe as single or multiple doses depending upon a variety of factors,including the drug's administered pharmacokinetic properties, the routeof administration, patient conditions and characteristics (sex, age,body weight, health, size, etc.), extent of symptoms, concurrenttreatments, frequency of treatment and the effect desired. In someembodiments, the formulation is designed for immediate release. In otherembodiments, the formulation is designed for sustained release. In otherembodiments, the formulation comprises one or more immediate releasesurfaces and one or more sustained release surfaces.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible,” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable,” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

In some embodiments, the drug depot has pores that allow release of thedrug from the depot. The drug depot will allow fluid in the depot todisplace the drug. However, cell infiltration into the depot will beprevented by the size of the pores of the depot. In this way, in someembodiments, the depot should not function as a tissue scaffold andallow tissue growth. Rather, the drug depot will solely be utilized fordrug delivery. In some embodiments, the pores in the drug depot will beless than 250 to 500 microns. This pore size will prevent cells frominfiltrating the drug depot and laying down scaffolding cells. Thus, inthis embodiment, drug will elute from the drug depot as fluid enters thedrug depot, but cells will be prevented from entering. In someembodiments, where there are little or no pores, the drug will elute outfrom the drug depot by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example, a bolus or immediate release formulation of clonidine maybe placed at or near the target site and a sustain release formulationmay also be placed at or near the same site. Thus, even after the bolusbecomes completely accessible, the sustain release formulation wouldcontinue to provide the active ingredient for the intended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-four toseventy-two hours after implantation. “Initial burst” or “burst effect”or “bolus dose” refers to the release of therapeutic agent from thedepot during the first twenty-four hours to seventy-two hours after thedepot comes in contact with an aqueous fluid (e.g., synovial fluid,cerebral spinal fluid, etc.). The “burst effect” is believed to be dueto the increased release of therapeutic agent from the depot. Inalternative embodiments, the depot (e.g., gel) is designed to avoid orreduce this initial burst effect (e.g., by applying an outer polymercoating to the depot).

“Treating” or “treatment” of a disease or condition refers to executinga protocol that may include administering one or more drugs to a patient(human, other normal or otherwise or other mammal), in an effort toalleviate signs or symptoms of the disease or condition. Alleviation canoccur prior to signs or symptoms of the disease or condition appearingas well as after their appearance. Thus, treating or treatment includespreventing or prevention of disease or undesirable condition. Inaddition, treating or treatment does not require complete alleviation ofsigns or symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingdystonia and/or post-stroke spasticity” includes a decrease in symptomsof dystonia or post-stroke spasticity and does not require completealleviation of dystonia or post-stroke spasticity signs or symptoms, anddoes not require a cure. In various embodiments, reducing dystonia orpost-stroke spasticity includes even a marginal decrease in dystonia orpost-stroke spasticity. By way of example, the administration of theeffective dosage of clonidine may be used to prevent, treat or relievethe symptoms of dystonia and/or post-stroke spasticity.

The term “implantable” as utilized herein refers to a biocompatibledevice (e.g., drug depot) retaining potential for successful placementwithin a mammal. The expression “implantable device” and expressions ofthe like import as utilized herein refers to an object implantablethrough surgery, injection, or other suitable means whose primaryfunction is achieved either through its physical presence or mechanicalproperties.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 0.1cm, or preferably within about 10 cm, for example) thereto. For example,the drug dose delivered locally from the drug depot may be, for example,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% lessthan the oral dosage or injectable dose. In turn, systemic side effects,such as for example, liver transaminase elevations, hepatitis, liverfailure, myopathy, constipation, etc. may be reduced or eliminated.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

The phrase “pain management medication” includes one or more therapeuticagents that are administered to prevent, alleviate or remove painentirely. These include anti-inflammatory agents, muscle relaxants,analgesics, anesthetics, narcotics, and so forth, and combinationsthereof.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, e.g., mcg/hr,mcg/day, 10% per day for ten days, etc. As persons of ordinary skillknow, a release rate profile may, but need not, be linear. By way of anon-limiting example, the drug depot may be a pellet that releases theclonidine over a period of time (see FIGS. 5-34).

The term “solid” is intended to mean a rigid material, while,“semi-solid” is intended to mean a material that has some degree offlexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

“Targeted delivery system” provides delivery of one or more drugsdepots, gels or depots dispersed in the gel having a quantity oftherapeutic agent that can be deposited at or near the target site asneeded for treatment of pain, inflammation or other disease orcondition.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide).

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to poly(ethylene glycol).

The abbreviation “PLGA” refers to poly(lactide-co-glycolide) also knownas poly(lactic-co-glycolic acid), which are used interchangeably.

The abbreviation “PLA” refers to polylactide.

The abbreviation “POE” refers to poly(orthoester).

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

Clonidine

When referring to clonidine, unless otherwise specified or apparent fromcontext, it is understood that the inventors are also referring topharmaceutically acceptable salts. One well-known commercially availablesalt for clonidine is its hydrochloride salt. Some other examples ofpotentially pharmaceutically acceptable salts include those salt-formingacids and bases that do not substantially increase the toxicity of acompound, such as, salts of alkali metals such as magnesium, potassiumand ammonium, salts of mineral acids such as hydriodic, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, as well as saltsof organic acids such as tartaric, acetic, citric, malic, benzoic,glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g.,p-toluenesulfonic acids, and the like.

Further, when referring to clonidine, the active ingredient may not onlybe in the salt form, but also in the base form (e.g., free base). Invarious embodiments, if it is in the base form, it may be combined withpolymers under conditions in which there is not severe polymerdegradation, as may be seen upon heat or solvent processing that mayoccur with PLGA or PLA. By way of a non limiting example, whenformulating clonidine with poly(orthoesters) it may be desirable to usethe clonidine base formulation. By contrast, when formulating clonidinewith PLGA, it may be desirable to use the HCl salt form. In someembodiments, clonidine may be incorporated into a polymer core with apolymer and then coated with the same or different polymer.

The clonidine or its pharmaceutically acceptable salt may beadministered with a muscle relaxant. Exemplary muscle relaxants includeby way of example and not limitation, alcuronium chloride, atracuriumbescylate, baclofen, carbamate, carbolonium, carisoprodol,chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium orcombinations thereof.

The drug depot may comprise other therapeutic agents in addition to theclonidine as well. These therapeutic agents, in various embodiments,block the transcription or translation of TNF-α or other proteins in theinflammation cascade. Suitable therapeutic agents include, but are notlimited to, integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, CTLA4-Igagonists/antagonists (BMS-188667), CD40 ligand antagonists, Humanizedanti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1 mAb (CriticalTherapeutics Inc.), anti-IL2R antibodies (daclizumab, basilicimab), ABX(anti IL-8 antibodies), recombinant human IL-10 or HuMax IL-15 (anti-IL15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogues (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression) andaurin-tricarboxylic acid (which inhibits TNF-α), may also be useful astherapeutic agents for reducing inflammation. It is further contemplatedthat where desirable a pegylated form of the above may be used. Examplesof still other therapeutic agents include NF kappa B inhibitors such asglucocorticoids, antioxidants such as dithiocarbamate, and othercompounds, such as, for example, sulfasalazine.

Examples of therapeutic agents suitable for use also include but are notlimited to an anti-inflammatory agent, an analgesic agent, or anosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, apazone, celecoxib, diclofenac,diflunisal, enolic acids (piroxicam, meloxicam), etodolac, fenamates(mefenamic acid, meclofenamic acid), gold, ibuprofen, indomethacin,ketoprofen, ketorolac, nabumetone, naproxen, nimesulide, salicylates,sulfasalazine [2-hydroxy-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid, sulindac, tepoxalin or tolmetin; as well as antioxidants, such asdithiocarbamate, steroids, such as fluocinolone, cortisol, cortisone,hydrocortisone, fludrocortisone, prednisone, prednisolone,methylprednisolone, triamcinolone, betamethasone, dexamethasone,beclomethasone, fluticasone or a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include butare not limited to a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Suitable analgesic agents include but are not limited to acetaminophen,bupivacaine, lidocaine, opioid analgesics such as buprenorphine,butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine,fentanyl, alfentanil, sufentanil, hydrocodone, hydromorphone,ketobemidone, levomethadyl, mepiridine, methadone, morphine, nalbuphine,opium, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol,codeine, dihydrocodeine, meptazinol, dezocine, eptazocine, flupirtine,amitriptyline, carbamazepine, gabapentin, pregabalin or a combinationthereof.

The clonidine may also be administered with non-active ingredients.These non-active ingredients may have multi-functional purposesincluding the carrying, stabilizing and controlling the release of thetherapeutic agent(s). The sustained release process, for example, may beby a solution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable.

Exemplary excipients that may be formulated with clonidine in additionto the biodegradable polymer include but are not limited to MgO (e.g., 1wt. %), 5050 DLG 6E (Lakeshore Biomaterials, Birmingham, Ala.), 5050 DLG1A (Lakeshore Biomaterials, Birmingham, Ala.), mPEG, TBO-Ac, mPEG,Span-65, Span-85, pluronic F127, TBO-Ac, sorbitol, cyclodextrin,maltodextrin, pluronic F68, CaCl, 5050 DLG-7A (Lakeshore Biomaterials,Birmingham, Ala.) and combinations thereof. In some embodiments, theexcipients comprise from about 0.001 wt. % to about 50 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 40 wt. % of the formulation. In some embodiments,the excipients comprise from about 0.001 wt. % to about 30 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 20 wt. % of the formulation. In some embodiments,the excipients comprise from about 0.001 wt. % to about 10 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 50 wt. % of the formulation. In some embodiments,the excipients comprise from about 0.001 wt. % to about 2 wt. % of theformulation.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to or greater than(for biodegradable components and non-biodegradable components) theplanned period of drug delivery.

In some embodiments, the depot material may have a melting point orglass transition temperature close to or higher than body temperature,but lower than the decomposition or degradation temperature of thetherapeutic agent. However, the pre-determined erosion of the depotmaterial can also be used to provide for slow release of the loadedtherapeutic agent(s). Non-biodegradable polymers include but are notlimited to PVC and polyurethane.

In some embodiments, the drug depot may not be fully biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics, methacrylates, poly (N-isopropylacrylamide), PEO-PPO-PEO(pluronics) or combinations thereof. Typically, these types of drugdepots may need to be removed after a certain amount of time.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioerodible, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release or sustained release of the clonidine. Examples ofsuitable sustained release biopolymers include but are not limited topoly(alpha-hydroxy acids), poly(lactide-co-glycolide), polylactide,polyglycolide (PG), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, polyhydroxybutyrate,poly(glycolide-co-trimethylenecarbonate), poly(lactic acid-co-lysine),poly(lactide-co-urethane), poly(ester-co-amide), PEG conjugates of poly(alpha-hydroxy acids), poly(orthoester)s, polyaspirins,polyphosphazenes, polyanhydrides; polyketals, collagen, starch,pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates,albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate,d-alpha tocopheryl succinate, ε-caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate) or combinations thereof. As persons of ordinaryskill are aware, mPEG may be used as a plasticizer for PLGA, but otherpolymers/excipients may be used to achieve the same effect. mPEG impartsmalleability to the resulting formulations. In some embodiments, thesebiopolymers may also be coated on the drug depot to provide the desiredrelease profile. In some embodiments, the coating thickness may be thin,for example, from about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 micronsto thicker coatings 60, 65, 70, 75, 80, 85, 90, 95, 100 microns to delayrelease of the drug from the depot. In some embodiments, the range ofthe coating on the drug depot ranges from about 5 microns to about 250microns or 5 microns to about 200 microns to delay release from the drugdepot.

As persons of ordinary skill in the art are aware, when an implantabledepot composition having a blend of polymers with different end groupsis used, the resulting formulation will have a lower burst index and aregulated duration of delivery. For example, one may use polymers withacid (e.g., carboxylic acid) and ester end groups (e.g., methyl or ethylester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer), there willbe a resulting depot composition having a regulated burst index andduration of delivery. For example, a depot composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot composition having apolymer with a L/G ratio of 65:35 may have a duration of delivery ofabout two months; a depot composition having a polymer with a L/G ratioof 75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot composition having a polymerratio with a L/G ratio of 85:15 may have a duration of delivery of aboutfive months; a depot composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% may have a duration of deliveryof about one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% may have a duration months upto six months. In general, increasing the G content relative to the CLcontent shortens the duration of delivery whereas increasing the CLcontent relative to the G content lengthens the duration of delivery.Thus, among other things, depot compositions having a blend of polymershaving different molecular weights, end groups and comonomer ratios canbe used to create a depot formulation having a lower initial burst and aregulated duration of delivery.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfite, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

The depot can be of different sizes, shapes and configurations. Thereare several factors that can be taken into consideration in determiningthe size, shape and configuration of the drug depot. For example, boththe size and shape may allow for ease in positioning the drug depot atthe target tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a pellet, aflat surface such as a disc, film or sheet (e.g., ribbon-like) or thelike. Flexibility may be a consideration so as to facilitate placementof the drug depot. In various embodiments, the drug depot can bedifferent sizes, for example, the drug depot may be a length of fromabout 0.5 mm to 5 mm and have a diameter of from about 0.01 to about 4mm. In various embodiments, as the diameter decreases, the surface areathat comes in contact with the bodily fluid of the depot increases andtherefore release of the drug from the depot increases. In variousembodiments, the drug depot may have a layer thickness of from about0.005 to 1.0 mm, such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium phosphate, bismuth, iodine, tantalum, tungsten and/ormetal beads or particles. In various embodiments, the radiographicmarker could be a spherical shape or a ring around the depot.

FIG. 1 illustrates a number of common locations within a patient thatmay be sites at which the clonidine may be administered. It will berecognized that the locations illustrated in FIG. 1 are merely exemplaryof the many different locations at which clonidine can be administered.For example, administration may be required at a patient's knees 21,hips 22, fingers 23, thumbs 24, neck 25 and/or spine 26.

Gel

In various embodiments, the clonidine is administered in a gel. The gelmay have a pre-dosed viscosity in the range of about 1 to about 2000centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After thegel is administered to the target site, the viscosity of the gel willincrease and the gel will have a modulus of elasticity (Young's modulus)in the range of about 1×−10² to about 6×10⁵ dynes/cm², 2×10⁴ to about5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In one embodiment, a depot comprises an adherent gel comprisingclonidine that is evenly distributed throughout the gel. The gel may beof any suitable type, as previously indicated, and should besufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted tissue site. The gel may, for example,solidify upon contact with the targeted tissue or after deployment froma targeted delivery system. The targeted delivery system may be, forexample, a syringe, a catheter, needle or cannula or any other suitabledevice. The targeted delivery system may inject the gel into or on thetargeted tissue site. The therapeutic agent may be mixed into the gelprior to the gel being deployed at the targeted tissue site. In variousembodiments, the gel may be part of a two-component delivery system andwhen the two components are mixed, a chemical process is activated toform the gel and cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×−10² to about 3×10⁵dynes/cm², 2×10⁴ to about 2×10⁵ dynes/cm² or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×−10² to about 2×10⁶ dynes/cm², 1×10⁵ to about 7×10⁵ dynes/cm² or2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polymer comprises 20 wt. % to90 wt. % of the formulation.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer versus non-polymer). For example, in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, incorporation of chain transfer or chaincapping agents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition thatincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers also tend to have a highersolution viscosity than a polymeric gel that includes low-molecularweight polymers. In various embodiments, the molecular weight of thepolymer can be a wide range of values. The average molecular weight ofthe polymer can be from about 1000 to about 10,000,000; or about 1,000to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 toabout 100,000; or about 20,000 to 50,000.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to high viscosity, similar to thatof a paste, depending on the molecular weight and concentration of thepolymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, when the polymers have similar componentsbut different MWs, a gel with a high molecular weight provides astronger matrix and the matrix takes more time to degrade. In contrast,a gel with a low molecular weight degrades more quickly and provides asofter matrix. In various embodiments, the gel has a molecular weight,as shown by the inherent viscosity, from about 0.10 dL/g to about 1.2dL/g or from about 0.10 dL/g to about 0.40 dL/g. Other IV ranges includebut are not limited to about 0.05 to about 0.15 dL/g, about 0.10 toabout 0.20 dL/g, about 0.15 to about 0.25 dL/g, about 0.20 to about 0.30dL/g, about 0.25 to about 0.35 dL/g, about 0.30 to about 0.35 dL/g,about 0.35 to about 0.45 dL/g, about 0.40 to about 0.45 dL/g, about 0.45to about 0.50 dL/g, about 0.50 to about 0.70 dL/g, about 0.60 to about0.80 dL/g, about 0.70 to about 0.90 dL/g, and about 0.80 to about 1.00dL/g.

In some embodiments, when the polymer materials have differentchemistries (e.g., high MW DLG 5050 and low MW DL), the high MW polymermay degrade faster than the low MW polymer.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, or from about 15 cps to about 75 cps at room temperature. Thegel may optionally have a viscosity enhancing agent such as, forexample, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof,Carbopol, poly-(hydroxyethylmethacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethyl methacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides or a combination thereof. Synthetichydrogels include but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with clonidine. In one embodiment, themicrospheres provide for a sustained release of the clonidine. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the clonidine; the microspheres thus do notrelease the clonidine until they have been released from the gel. Forexample, a gel may be deployed around a target tissue site (e.g., anerve root). Dispersed within the gel may be a plurality of microspheresthat encapsulate the desired therapeutic agent. Certain of thesemicrospheres degrade once released from the gel, thus releasing theclonidine.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse theclonidine. In some situations, this may be desirable; in others, it maybe more desirable to keep the clonidine tightly constrained to awell-defined target site. The present invention also contemplates theuse of adherent gels to so constrain dispersal of the therapeutic agent.These gels may be deployed, for example, in a disc space, in a spinalcanal or in surrounding tissue.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device, e.g., a syringe, a gun drugdelivery device or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes but is not limited to from about0.05 to about 1.655 (mm). The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include but are not limited to barium, bismuth, tantalum,tungsten, iodine, calcium, and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, X-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requiresindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including but not limited to gassterilization, such as, for example, with ethylene oxide or steamsterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot. The kit may include the drug depotdevice in a first compartment. The second compartment may include acanister holding the drug depot and any other instruments needed for thelocalized drug delivery. A third compartment may include gloves, drapes,wound dressings and other procedural supplies for maintaining sterilityof the implanting process, as well as an instruction booklet. A fourthcompartment may include additional cannulas and/or needles. A fifthcompartment may include an agent for radiographic imaging. Each tool maybe separately packaged in a plastic pouch that is radiation sterilized.A cover of the kit may include illustrations of the implanting procedureand a clear plastic cover may be placed over the compartments tomaintain sterility.

In various embodiments, a method for delivering a therapeutic agent intoa site of a patient is provided, the method comprising inserting acannula at or near a target tissue site and implanting the drug depot atthe target site beneath the skin of the patient and brushing, dripping,injecting, or painting the gel in the target site to hold or have thedrug depot adhere to the target site. In this way, unwanted migration ofthe drug depot away from the target site is reduced or eliminated.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target tissuesite and the gel administered at or near the target site. In thoseembodiments, where the drug depot is separate from the gel, first thecannula or needle can be inserted through the skin and soft tissue downto the site of injection and one or more base layer(s) of gel can beadministered to the target site. Following administration of the one ormore base layer(s), the drug depot can be implanted on or in the baselayer(s) so that the gel can hold the depot in place or reducemigration. If required, a subsequent layer or layers of gel can beapplied on the drug depot to surround the depot and further hold it inplace. Alternatively, the drug depot may be implanted first and then thegel placed around the drug depot to hold it in place. By using the gel,accurate and precise implantation of a drug depot can be accomplishedwith minimal physical and psychological trauma to the patient. The gelalso avoids the need to suture the drug depot to the target sitereducing physical and psychological trauma to the patient.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through the cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

One exemplary embodiment where the depot is suitable for use in treatingpost-stroke spasticity is illustrated in FIG. 2. Schematically shown inFIG. 2 is a dorsal view of the spine 30 and sites where the drug depotmay be inserted using a cannula or needle beneath the skin 34 to aspinal site 32 (e.g., spinal disc space, spinal canal, soft tissuesurrounding the spine, nerve root, etc.) and one or more drug depots 28and 32 are delivered to various sites along the spine. In this way, whenseveral drug depots are to be implanted, they are implanted in a mannerthat optimizes location, accurate spacing, and drug distribution.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including but not limitedto at least one muscle, ligament, tendon, the cervical part of thespine, cartilage, a spinal disc, a spinal foraminal space, near thespinal nerve root and the spinal canal.

In some embodiments, it is preferable to co-administer clonidine with anantagonist to counteract undesirable effects, for example, the bloodpressure decrease that can be caused by clonidine. Exemplary antagonistsinclude but are not limited to phentolamine, yohimbine, tolazoline andpiperoxane. Additionally, compounds such as 5-fluorodeoxyuridine (FUDR)and 3,4 dehydroprolene may also be included. These compounds may preventor reduce glial and fibroblastic scar formation associated with sometypes of surgeries.

The clonidine-based formulation of the present application may be usedas medicaments in the form of pharmaceutical preparations. Thepreparations may be formed in an administration with a suitablepharmaceutical carrier that may be solid or liquid and organic orinorganic, and placed in the appropriate form for parenteral or otheradministration as desired. As persons of ordinary skill are aware, knowncarriers include but are not limited to water, saline solution, gelatin,lactose, starches, stearic acid, magnesium stearate, sicaryl alcohol,talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol,polyalkylene glycols and other known carriers for medicaments.

Parenteral administration may additionally include, for example, aninfusion pump that administers a pharmaceutical composition (e.g.,analgesic and anti-inflammatory combination) through a catheter near thespine or one or more inflamed joints, an implantable mini-pump that canbe inserted at or near the target site, an implantable controlledrelease device or sustained release delivery system that can release acertain amount of the statin per hour or in intermittent bolus doses.One example of a suitable pump for use is the SynchroMed® (Medtronic,Minneapolis, Minn.) pump. This pump has three sealed chambers. Onecontains an electronic module and battery. The second contains aperistaltic pump and drug reservoir. The third contains an inert gasthat provides the pressure needed to force the pharmaceuticalcomposition into the peristaltic pump. To fill the pump, thepharmaceutical composition is injected through the reservoir fill portto the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously,continually, at specific times, or at set intervals between deliveries.

Another embodiment is directed to a method for treating a mammalsuffering from dystonia and/or post-stroke spasticity, the methodcomprising administering a therapeutically effective amount of clonidineat a target site beneath the skin. The clonidine (or pharmaceuticallyacceptable salt) may for example be administered locally to the targettissue site as a drug depot.

In some embodiments, the clonidine is suitable for parenteraladministration. The term “parenteral” as used herein refers to modes ofadministration that bypass the gastrointestinal tract, and include forexample, intravenous, intramuscular, continuous or intermittentinfusion, intraperitoneal, intrasternal, subcutaneous,intra-operatively, intrathecally, intradiscally, peridiscally,epidurally, perispinally, intraarticular injection or combinationsthereof. In some embodiments, the injection is intrathecal, which refersto an injection into the spinal canal (intrathecal space surrounding thespinal cord). An injection may also be into a muscle or other tissue.

In various embodiments, the drug depot comprising the clonidine can bemade by combining a biocompatible polymer and a therapeuticallyeffective amount of clonidine or pharmaceutically acceptable saltthereof and forming the implantable drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s) andoptional materials including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: clonidine and other therapeuticagent(s) and other optional additives such as radiographic agent(s),etc. in dissolved or dispersed form. This results in a polymeric matrixregion containing these species after solvent removal. In otherembodiments, a solution containing solvent with dissolved or dispersedtherapeutic agent is applied to a pre-existing polymeric region, whichcan be formed using a variety of techniques including solutionprocessing and thermoplastic processing techniques, whereupon thetherapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: clonidine,optional additional therapeutic agent(s), radiographic agent(s), and soforth. The resulting mixture is then shaped into an implantable drugdepot. The mixing and shaping operations may be performed using any ofthe conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, clonidine may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding a biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer ispre-compounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This pre-compounded material is then mixed with a therapeutic agentunder conditions of lower temperature and mechanical shear, and theresulting mixture is shaped into the clonidine containing drug depot.Conversely, in another embodiment, the biocompatible polymer can bepre-compounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This pre-compounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., clonidine), invarious embodiments, the PGLA or PLA can be premixed with theradio-opacifying agent at temperatures of about, for example, 150° C. to170° C. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the therapeutic agent(s). For instance, the therapeuticagent and premixed composition can be mixed/compounded using a twinscrew extruder at substantially lower temperatures (e.g., 100-105° C.),and using substantially reduced volumetric output (e.g., less than 30%of full capacity, which generally corresponds to a volumetric output ofless than 200 cc/min). It is noted that this processing temperature iswell below the melting points of clonidine because processing at orabove these temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble therapeutic agent such as clonidine is used, theimmersion time should be held to a minimum to avoid unnecessary loss oftherapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, clonidine is used and mixed orsprayed with the PLGA or PEG550 polymer, and the resulting depot may beformed by extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: clonidine, wherein the clonidine comprises from about 0.1wt. % to about 30 wt. % of the formulation, and at least onebiodegradable polymer. In some embodiments, the clonidine comprises fromabout 3 wt. % to about 20 wt. %, about 3 wt. % to about 18 wt. %, about5 wt. % to about 15 wt. % or about 7.5 wt. % to about 12.5 wt. % of theformulation. By way of an example, when using a 5%-15% clonidinecomposition, the mole ratio of clonidine to polymer would be fromapproximately 16-53 when using an approximately 80 kDalton polymer thathas a 267 grams/mole ratio. By way of another example, when using a5%-15% clonidine base in the composition, the mole ratio of clonidinebase to polymer would be from approximately 18-61 with a mole mass of230 g/mol.

In some embodiments, the drug depot comprises at least one biodegradablematerial in a wt. % of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%,78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%, 35%,25%, 20%, 15%, 10%, or 5% based on the total weight of the depot and theremainder is active and/or inactive pharmaceutical ingredients.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolide), poly(orthoester) or a combination thereof.The poly(lactic-co-glycolide) may comprise a mixture of polyglycolideand polylactide and in some embodiments, in the mixture, there is morepolylactide than polyglycolide. In various embodiments, there is 100%polylactide and 0% polyglycolide; 95% polylactide and 5% polyglycolide;90% polylactide and 10% polyglycolide; 85% polylactide and 15%polyglycolide; 80% polylactide and 20% polyglycolide; 75% polylactideand 25% polyglycolide; 70% polylactide and 30% polyglycolide; 65%polylactide and 35% polyglycolide; 60% polylactide and 40%polyglycolide; 55% polylactide and 45% polyglycolide; 50% polylactideand 50% polyglycolide; 45% polylactide and 55% polyglycolide; 40%polylactide and 60% polyglycolide; 35% polylactide and 65%polyglycolide; 30% polylactide and 70% polyglycolide; 25% polylactideand 75% polyglycolide; 20% polylactide and 80% polyglycolide; 15%polylactide and 85% polyglycolide; 10% polylactide and 90%polyglycolide; 5% polylactide and 95% polyglycolide; or 0% polylactideand 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide,there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, the drug particle size (e.g., clonidine) is fromabout 5 to 30 micrometers, however, in various embodiments ranges fromabout 1 micron to 250 microns may be used. In some embodiments, thebiodegradable polymer comprises at least 50 wt. %, at least 60 wt. %, atleast 70 wt. %, at least 80 wt. % of the formulation, at least 85 wt. %of the formulation, at least 90 wt. % of the formulation, at least 95wt. % of the formulation or at least 97 wt. % of the formulation. Insome embodiments, the at least one biodegradable polymer and theclonidine are the only components of the pharmaceutical formulation.

In some embodiments, at least 75% of the particles have a size fromabout 10 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 10 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 180 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 180 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 180 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 180 micrometers.

In some embodiments, there is a pharmaceutical formulation comprisingclonidine, wherein the clonidine is in a mixture of clonidinehydrochloride and clonidine base and the mixture comprises from about0.1 wt. % to about 30 wt. % of the formulation and a polymer comprisesat least 70% of the formulation. In some embodiments, the polymer inthis formulation is polyorthoester.

In some embodiments, the formulation comprises a drug depot thatcomprises a biodegradable polyorthoester. The mechanism of thedegradation process of the polyorthoester can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface of the drug depot (heterogeneous orsurface erosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion). Polyorthoester can be obtained from A.P.Pharma, Inc. (Redwood City, Calif.) or through the reaction of abis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties.

In some embodiments, there are methods for treating dystonia and/orpost-stroke spasticity. These methods comprise: administering apharmaceutical composition to an organism, wherein the pharmaceuticalcomposition comprises from about 0.1 wt. % to about 30 wt. % of theformulation, and at least one biodegradable polymer. In someembodiments, the loading is from about 1 wt. % to about 25 wt. %, orabout 5 wt. % to about 10 wt. %. In some embodiments, the loading isfrom about 10 wt. % to about 20 wt. %.

In some embodiments, there is a higher loading of clonidine, e.g., atleast 20 wt. %, at least 30 wt. %, at least 40 wt. %, at least 50 wt. %,at least 60 wt. %, at least 70 wt. %, at least 80 wt. % or at least 90wt. %.

A strategy of triangulation may be effective when administering thesepharmaceutical formulations. Thus, a plurality (at least two, at leastthree, at least four, at least five, at least six, at least seven, etc.)of drug depots comprising the pharmaceutical formulations may be placedaround the target site such that the target tissue site falls within aregion that is either between the formulations when there are two, orwithin an area whose perimeter is defined by a set of plurality offormulations.

In some embodiments, the formulations are slightly rigid with varyinglength, widths, diameters, etc. For example, certain formulations mayhave a diameter of 0.50 mm and a length of 4 mm. It should be noted thatparticle size may be altered by techniques such as mort and pestle,jet-drying or jet milling.

In some embodiments, clonidine is released at a rate of 2-3 μg per dayfor a period of at least three days. In some embodiments, this releaserate continues for at least ten days, at least fifteen days, at leasttwenty-five days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days or at least one hundred and eighty days. Forsome embodiments, 300-425 micrograms of clonidine as formulated with abiopolymer are implanted into a person at or near a target tissue site.If clonidine is implanted at multiple sites that triangulate the targetsite, then in some embodiments, the total amount of clonidine at eachsite is a fraction of the total 300-425 micrograms. For example, one mayimplant a single dose of 324 micrograms at one site, or two separatedoses of 162 micrograms at two sites, or three separate doses of 108micrograms at three sites that triangulate the tissue site. It isimportant to limit the total dosage to an amount less than that whichwould be harmful to the organism. However, in some embodiments, althoughwhen there are a plurality of sites each site may contain less than thetotal dose that might have been administered in a single application, itis important to remember that each site will independently have arelease profile, and the biopolymers' concentration and substance shouldbe adjusted accordingly to ensure that the sustain release occurs oversufficient time.

The dosage may be from approximately 0.0005 to approximately 960 μg/day.Additional dosages of clonidine include from approximately 0.0005 toapproximately 900 μg/day; approximately 0.0005 to approximately 500μg/day; approximately 0.0005 to approximately 250 μg/day; approximately0.0005 to approximately 100 μg/day; approximately 0.0005 toapproximately 75 μg/day; approximately 0.001 to approximately 70 μg/day;approximately 0.001 to approximately 65 μg/day; approximately 0.001 toapproximately 60 μg/day; approximately 0.001 to approximately 55 μg/day;approximately 0.001 to approximately 50 μg/day; approximately 0.001 toapproximately 45 μg/day; approximately 0.001 to approximately 40 μg/day;approximately 0.001 to approximately 35 μg/day; approximately 0.0025 toapproximately 30 μg/day; approximately 0.0025 to approximately 25μg/day; approximately 0.0025 to approximately 20 μg/day; approximately0.0025 to approximately 15 μg/day; approximately 0.0025 to approximately10 μg/day; approximately 0.0025 to approximately 5 μg/day; andapproximately 0.0025 to approximately 2.5 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 15μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 10 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 5μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 2.5 μg/day. In some embodiments,the amount of clonidine is between 40 and 600 μg/day. In someembodiments, the amount of clonidine is between 200 and 400 μg/day.

In some embodiments, the therapeutically effective dosage amount (e.g.,clonidine dose) and the release rate profile are sufficient to reducedystonia and/or post-stroke spasticity for a period of at least one day,1-90 days, 1-10 days, 1-3 days, 3-7 days, 3-12 days; 3-14 days, 7-10days, 7-14 days, 7-21 days, 7-30 days, 7-50 days, 7-90 days, 7-140 days,14-140 days, 3 days to 135 days, 3 days to 180 days, or 3 days to 6months or 1 year or longer.

In some embodiments, the clonidine depot is designed for a bolus dose orburst dose within 1, 2 or 3 days after implantation to provide animmediate release of the clonidine for treatment of dystonia and/orpost-stroke spasticity.

In some embodiments, the clonidine depot is administered parenterally,e.g., by injection. In some embodiments, the injection is intrathecal,which refers to an injection into the spinal canal (intrathecal spacesurrounding the spinal cord). An injection may also be into a muscle orother tissue. In other embodiments, the clonidine depot is administeredby placement into an open patient cavity during surgery.

In some embodiments, the drug depot (i) comprises one or more immediaterelease layer(s) that is capable of releasing about 5% to about 20% ofthe clonidine or pharmaceutically acceptable salts thereof relative to atotal amount of the clonidine or pharmaceutically acceptable saltthereof loaded in the drug depot over a first period of up to 48 hoursand (ii) one or more sustain release layer(s) that is capable ofreleasing about 21% to about 99% of the clonidine or pharmaceuticallyacceptable salt thereof relative to a total amount of the clonidine orpharmaceutically acceptable salt thereof loaded in the drug depot over asubsequent period of up to 3 days to 90 days, 150 days, 180 days or 6months to 1 year.

In one exemplary dosing regimen, a rat may be provided with sufficientclonidine in a biodegradable polymer to provide sustain release of 0.240μg/day for 135 days. The total amount of clonidine that is administeredover this time period would be approximately 32.4 μg. In anotherexemplary dosing regimen, a human is provided with sufficient clonidinein a biodegradable polymer to provide sustain release of 2.4 μg/day for135 days. The total amount of clonidine that is administered over thistime period would be approximately 324 μg.

When using a plurality of pellets, the pellet number is based on theamount of drug loading into a pellet of appropriate size (i.e., 0.5 mmdiameter×4 mm length) and how much drug is needed (e.g., approximately325 μg clonidine (3 pellets)). In some embodiments, there is a polymerthat releases a bolus amount of compound over the first few (˜5) daysbefore it settles down and releases 2.5 mg/day for 135 days. Anexemplary formulation is 5 wt. % clonidine, 100 DL 5E (LakeshoreBiomaterials, Birmingham, Ala.).

In some embodiments, the polymer depots of the present invention enableone to provide efficacy of the active ingredient that is equivalent tosubcutaneous injections that deliver more than 2.5 times as much drug.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES

The examples below show certain particularly advantageous resultswherein the initial burst is not too large (i.e., not more than 7% ofthe load drug in the first five days) and the daily dose isapproximately 2.4 μg/day±0.5 μg/day for 135 days. See e.g., FIGS. 12,13, 14 and 19. The figures further demonstrate that drug loadings 5 wt.% to 8 wt. % provide advantageous results.

A 2-month chronic constriction injury (CCI) model of neuropathic painwas used to evaluate different formulations of clonidine encapsulated inbioerodible polymers compared to clonidine given subcutaneously (SC).Different formulations as provided in Table 5 below were evaluated forreducing pain-associated behaviors: Thermal paw withdrawal latency wasevaluated at baseline, 7, 14, 21, 28, 35, 42, 49, 56 and 64 dayspost-operatively, while mechanical threshold was evaluated at 8, 15, 22,29, 36, 43, 50, 57 and 64 days post-operatively. Bar graphs depictingthe results of theses tests are shown in FIGS. 3-4.

FIG. 3 is a graphic representation of the thermal paw withdrawal latencyas a percentage from baseline for the following administrations:clonidine 0.02 mg/kg/day subcutaneously, 100 DL 7E Control, 5% CL-HCL,CL 5%, CL 8%, 1 CL 7%, POE Control and POE CL-Base, at 7 days, 14 days,21 days, 28 days, 35 days, 42 days, 49 days, 56 days and 63 days. CL-HCLrefers to clonidine hydrochloride. “POE” refers to poly(orthoester).“CL-Base” refers to clonidine in its base form. The clonidineformulations reduced the pain threshold in the animals tested.

FIG. 4 is a graphic representation of the mechanical threshold as apercentage from baseline for the following administrations: clonidine0.02 mg/kg/day subcutaneously, 100 DL 7E Control, 5% CL-HCL, CL 5%, CL8%, CL 7%, POE Control and POE CL-Base, at 8 days, 15 days, 22 days, 29days, 36 days, 43 days, 50 days, 57 days and 64 days. The clonidineformulations reduced the pain threshold in the animals tested.

In Vitro elution studies were carried out at 37° C. inphosphate-buffered saline (PBS, pH 7.4). Briefly, the rods (n=3) wereweighed prior to immersion in 5 mL of PBS. At regular time intervals,the PBS was removed for analysis and replaced with 5 mL of fresh PBS.The PBS-elution buffer was analyzed for clonidine content using UV-Visspectrometry.

Example 1 Formulation Testing

The inventors prepared a number of clonidine formulations in which theyvaried the polymer type, drug load, excipient (including someformulations in which there was no excipient), pellet size andprocessing. These formulations are described below in Table 1, Table 2and Table 3. A number of tests were performed on these formulations,including in vitro release tests in which the number of microgramsreleased was measured, as well as the cumulative percentage release ofclonidine. The results of these tests appear in FIGS. 5-36.

FIG. 5 is a graphic representation of a study of the cumulative releaseby percentage of clonidine HCl sterilized formulations for an in vivoefficacy study mentioned in FIGS. 3 and 4. In FIG. 5, the formulations(first three of Table 3) contained: 8.1 wt. % clonidine, the remainder100 DL 5E (the inherent viscosity of the 100 DL was 0.45-0.55 and had anester end group), or 7.2 wt. % clonidine, the remainder 100 DL 7E (theinherent viscosity of the 100 DL was 0.60-0.80 and had an ester endgroup) or 5 wt. % clonidine, the remainder 100 DL 5E (the inherentviscosity of the 100 DL was 0.45-0.55 and had an ester end group). Theformulations with the higher drug loads released the fastest over 70days, with a cumulative release of 45% and 80%. The formulation with 5%clonidine drug load released drug the longest for over 160 days and hada cumulative release of 95% of the drug.

FIG. 6 is an in vitro graphic representation of studies of thepercentage daily release profiles of sterilized clonidine formulationsof FIG. 5 (first three of Table 3) and their cumulative average dailyrelease of the three formulations in micrograms per day. Each drug depothad an initial burst effect with a release of clonidine over 50 mcg forthe first day. These calculations are based on 3 pellets implanted(which would approximate the dose of clonidine in humans). The pelletsranged in size from 0.5 mm to about 1 mm in diameter and 3-4 mm inlength, which would be small enough to place in a needle. Theformulations with the higher drug loads released the fastest over 70days, where the drug dose released was about 5 mcg to about 0.1 mcg/dayafter about the first 30 days and the formulation with the lowest drugload of about 5% clonidine released the longest for a period of over 160days, where the release was consistently between about 5 mcg to 0.1mcg/day after about day 30. The target daily dose was 2.4 mcg/day andthe formulation with the 5% clonidine drug load came closest to thistarget daily dose.

In vitro elution studies were carried out at 37° C. inphosphate-buffered saline (PBS, pH 7.4). The rods (n=3) were weighedprior to immersion in 5 mL of PBS. At regular time intervals, the PBSwas removed for analysis and replaced with 5 mL of fresh PBS. ThePBS-elution buffer was analyzed for clonidine content using UV-Visspectrometry.

TABLE 1 Drug Pellet Size Load (L × Dia; mm) Notebook ID Polymer Type(Wt. %) Excipient or Description Processing 13335-60-1 8515 DLG 7E 10N/A 0.75 × 0.75 Melt extrusion, co-spray dried drug/polymer 13335-60-28515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, spray dried drug13335-60-3 8515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, hand grounddrug 13335-60-4 8515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, handground drug, spray dried polymer 13335-60-5 8515 DLG 7E 10 N/A 0.75 ×0.75 Melt extrusion w/recycle loop, hand ground drug 13335-65-1 8515 DLG7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-65-2 8515DLG 7E 10 N/A  1.5 × 0.75 Melt extrusion, spray dried drug 13335-65-38515 DLG 7E 20 N/A 0.75 × 0.75 Melt extrusion, spray dried drug13335-65-4 100 DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug13335-65-5 100 DL 7E 10 N/A  1.5 × 0.75 Melt extrusion, spray dried drug13335-65-6 100 DL 7E 20 N/A 0.75 × 0.75 Melt extrusion, spray dried drug13335-97-1 8515 DLG 7E 7.5 N/A  3.0 × 0.75 Melt extrusion, spray drieddrug 13335-97-2 100 DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray drieddrug 13335-97-3 8515 DLG 7E 5 10% mPEG  3.0 × 0.75 Melt extrusion, spraydried drug 13335-97-4 100 DL 7E 5 10% mPEG  3.0 × 0.75 Melt extrusion,spray dried drug 13699-1-1 100 DL 7E 5 N/A  3.0 × 0.75 Melt extrusion,spray dried drug 13699-16-1 8515 DLG 7E 10 N/A  1.5 × 0.75 Meltextrusion, spray dried drug 13699-16-2 9010 DLG 7E 10 N/A  1.5 × 0.75Melt extrusion, spray dried drug 13699-16-3 9010 DLG 7E 5 N/A  3.0 ×0.75 Melt extrusion, spray dried drug 13699-16-4 8515 DLG 7E 5 5% mPEG 3.0 × 0.75 Melt extrusion, spray dried drug 13699-16-5 8515 DLG 7E 52.5% mPEG  3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-1 8515DLG 7E 5 1% MgO  3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-48515 DLG 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug13699-20-5 100 DL 7E 5 10% 5050  3.0 × 0.75 Melt extrusion, spray drieddrug DLG 6E 13699-20-6 100 DL 7E 5 10% 5050  3.0 × 0.75 Melt extrusion,spray dried drug DLG 1A 13699-20-7 8515 DLG Purac 10 N/A  1.5 × 0.75Melt extrusion, spray dried drug 13699-20-8 8515 DLG 7E 5 N/A  3.0 ×0.75 Melt extrusion 2X, spray dried drug 13699-28-1 8515 DLG Purac 7.5N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13699-28-2 8516 DLGPurac 12.5 N/A  2.0 × 0.75 Melt extrusion, spray dried drug 13699-28-3100 DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13699-31-18515 DLG 7E 10 N/A N/A heat press, spray dried drug 13699-31-2 8515 DLG7E 10 N/A N/A heat press, spray dried drug 13699-31-3 8515 DLG 7E 10 N/AN/A heat press, spray dried drug 13699-31-4 8515 DLG 7E 10 N/A N/A Meltextrusion, spray dried drug 12702-13-4-a 1,6-Hexanediol/ 10 N/A 3 × 3Melt extrusion tCHDM 12702-13-4-b 75/25 PLGA 10 N/A 3 × 3 Melt extrusion12702-68-12 75/25 PLGA 5 mPEG 1 × 1 Melt extrusion 12702-68-13 75/25PLGA 5 TBO-Ac 1 × 1 Melt extrusion 12702-72-1 75/25 PLGA 5 mPEG 1 × 1Melt extrusion 12702-80-7 75/25 PLGA 10 mPEG 0.75 × 0.75 Melt extrusion12702-80-8 75/25 PLGA 15 mPEG 0.75 × 0.75 Melt extrusion 13395-3-1 85/15PLGA 10 mPEG 0.75 × 0.75 Melt extrusion 13395-3-2 85/15 PLGA 15 mPEG0.75 × 0.75 Melt extrusion 13395-3-3 85/15 PLGA 5 mPEG 0.75 × 0.75 Meltextrusion 13395-15 85/15 PLGA 15 mPEG 0.75 × 0.75 Melt extrusion13395-20-1 85/15 PLGA 5 Span-85 0.75 × 0.75 Melt extrusion 13395-20-285/15 PLGA 5 Pluronic- 0.75 × 0.75 Melt extrusion F127 13395-20-3 85/15PLGA 5 N/A 0.75 × 0.75 Melt extrusion 13395-21-1 D,L-PLA 5 mPEG 0.75 ×0.75 Melt extrusion 13395-21-2 85/15 PLGA 5 TBO-Ac 0.75 × 0.75 Meltextrusion 13395-24-1 85/15 PLGA 5 Span-65 0.75 × 0.75 Melt extrusion13395-27-1 85/15 PLGA 10 N/A 0.75 × 0.75 Melt extrusion 13395-27-2 85/15PLGA 15 N/A 0.75 × 0.75 Melt extrusion 13395-27-3 85/15 PLGA 10 Span-650.75 × 0.75 Melt extrusion 13395-27-4 85/15 PLGA 10 TBO-Ac 0.75 × 0.75Melt extrusion 13395-27-5 85/15 PLGA 10 Pluronic 0.75 × 0.75 Meltextrusion F127 13395-34-2 D,L-PLA 10 N/A 0.75 × 0.75 Melt extrusion13395-34-3 D,L-PLA 10 TBO-Ac 0.75 × 0.75 Melt extrusion 13395-34-4D,L-PLA 10 mPEG 0.75 × 0.75 Melt extrusion 13395-42-1 DL-PLA/PCL 10 N/A0.75 × 0.75 Melt extrusion 13395-42-2 DL-PLA/PCL 15 N/A 0.75 × 0.75 Meltextrusion

TABLE 2 Drug Pellet Size Load (L × Dia; mm) Notebook ID Polymer Type(Wt. %) Excipient or Description Processing 13335-73-1 POE 58 10 N/A 1.5 × 0.75 Melt extrusion 13335-73-2 POE 58 20 N/A 0.75 × 0.75 Meltextrusion 13335-73-3 POE 60 10 N/A  1.5 × 0.75 Melt extrusion 13335-73-4POE 60 20 N/A 0.75 × 0.75 Melt extrusion 13699-1-2 POE 58 10 N/A 4-1.5 ×0.75  Melt extrusion 13699-1-3 POE 58 20 N/A 1-0.75 × 0.75  Meltextrusion 12702-23 tCHDM (100) 25 N/A Microspheres Double emulsion12702-26 tCHDM/DET 4.2 N/A Microspheres Double emulsion (70/30) 12702-5475/25 PLGA 20 N/A Microspheres Double emulsion 12702-68-9 75/25 PLGA 5mPEG 3 × 3 Melt extrusion 12702-68-10 75/25 PLGA 5 TBO-Ac 3 × 3 Meltextrusion 12702-87 75/25 PLGA 15 mPEG Mixer-Molder 12702-90 85/15 PLGA17 N/A Mixer-Molder 12702-78-1 Polyketal 7 N/A 2 × 3 Melt extrusion(12833-14-1) 13395-14 50/50 PLGA (2A) 10 mPEG N/A Melt extrusion13395-17-1 POE (13166-75) 5 N/A 1.5 × 1.5 Melt extrusion 13395-17-2 POE(13166-77) 5 N/A 1.5 × 1.5 Melt extrusion 13395-47-1 DL-PCL 10 N/A 1.3 ×1.3 Melt extrusion 13395-50 DL-PCL 10 N/A 1.3 × 1.3 Melt extrusion;w/solvent prep 13395-51 D,L-PLA 10 mPEG N/A Melt extrusion

TABLE 3 Drug Load Notebook ID Polymer Type (Wt. %) Processing 00178-23100 DL 5E 8.1 Melt extrusion, hand mixed 00178-15 100 DL 7E 7.2 Meltextrusion, hand mixed 00178-35 100 DL 5E 5 Melt extrusion, hand mixed00178-16 100 DL 7E 10.2 Melt extrusion, hand mixed 00178-21 8515 DL 7E7.3 Melt extrusion, hand mixed 00178-36 100 DL 7E 5 Melt extrusion, handmixed 00178-44 100 DL 7E 5.1 Dissolved in glacial acetic acid, freezedried, melt extrusion 00178-45 100 DL 7E 4.5 Drug and polymer blend,prepared in N2 environment, melt extrusion 00178-45-C 100 DL 7E 4.5Formulation 00178-45 with EtOAc coating 00178-63 100 DL 7E 9.4 Meltextrusion 00178-08 100 DL 7E 21.4 melt extrusion, no reduction in drugparticle size 00178-11 100 DL 7E 7.9 melt extrusion, no reduction indrug particle size 00178-12 100 DL 7E 11.7 melt extrusion, no reductionin drug particle size 00178-22 8515 DL 7E 8.3 melt extrusion 00178-24100 DL 5E 10.1 melt extrusion 00178-23-C 100 DL 5E 8.1 Formulation00178-23 with EtOAc coating 00178-23-PC 100 DL 5E 8.1 Formulation00178-23 with polymer solution coating 00178-35-C 100 DL 5E 5Formulation 00178-35 with EtOAc coating 00178-36-C 100 DL 7E 5Formulation 00178-36 with EtOAc coating 00178-72 100 DL 7E 4.5 DoubleExtrusion (20% diluted to 5%) 00178-73 100 DL 7E 8.7 Double Extrusion(20% diluted to 10%) 00178-74 6353 DLG 7E 7.3 Melt extrusion, hand mixed00178-71 6535 DLG 7E 5.3 Melt extrusion, hand mixed 00178-75 6535 DLG 7E3.3 Melt extrusion, hand mixed 00178-76-R1 100 DL 7E core with 7.76coaxial extrusion, 4 different coating thicknesses 100DL 5E coating00178-76-R2 100 DL 7E core 6.92 coaxial extrusion, 4 different coatingthicknesses with 100DL 5E coating 00178-76-R3 100 DL 7E core 6.76coaxial extrusion, 4 different coating thicknesses with 100DL 5E coating00178-76-R4 100 DL 7E core 8 coaxial extrusion, 4 different coatingthicknesses with 100DL 5E coating 00178-79-R1 100 DL 5E core with 12.1coaxial extrusion, thin coat 100DL 5E coating 00178-80-R1 100 DL 5E corewith 7.54 coaxial extrusion, different coating thicknesses 100DL 5Ecoating 00178-80-R3 100 DL 5E core with 8.9 coaxial extrusion, differentcoating thicknesses 100DL 5E coating 00178-80-R4 100 DL 5E core with10.0 coaxial extrusion, different coating thicknesses 100DL 5E coating00178-77 100 DL 5E 5.2 repeat of 178-35 (1.0 mm diameter) 00178-78 100DL 5E 5.1 repeat of 178-35 (0.8 mm diameter) 00178-81 100 DL 5E 7.2repeat of 178-23 00178-87 100 DL 5E 5.0 Repeat of 178-35 (1.0 mm diam)00178-90 100 DL 5E 5 Repeat 178-35, mechanical mixing, single screw meltextrusion (0.8 mm and 1.0 mm diameter) 00178-91-R1 100 DL 5E core with3.5 Coaxial extrusion, thick coating 100DL 5E coating 00178-91-R6 100 DL5E core with 7.4 Coaxial extrusion, thin coating 100DL 5E coating00178-93-R3 100 DL 5E core with 5 Coaxial extrusion, mechanical mixing,thin coating layer 100DL 7E coating 00178-93-R4 100 DL 5E core with 3.8Coaxial extrusion, mechanical mixing, thick coating layer 100DL 7Ecoating

The codes within the table for the polymer are explained as follows. Thefirst number or numbers refer to the monomer mole percentage ratio ofDL-lactide (e.g., polylactide) to glycolide (e.g., poly-glycolide). Theletter code that follows the first number refers to the polymer(s) andis the polymer identifier. The second number, which follows the lettercode for the polymer, is the target IV designator and is 10 times themidpoint of a range in dl/g. The meanings of certain IV designators arereflected in Table 4.

TABLE 4 IV Target Designator IV Range 1 0.05-0.15 1.5 0.10-0.20 20.15-0.25 2.5 0.20-0.30 3 0.25-0.35 3.5 0.30-0.40 4 0.35-0.45 4.50.40-0.50 5 0.45-0.55 6 0.50-0.70 7 0.60-0.80 8 0.70-0.90 9 0.80-1.0 

The final letter within the code of the polymer is the end groupdesignator. For example, “E” refers to an ester end group, while “A”refers to an acid end group.

By way of example, 100 DL7E is a polymer that has an inherent viscosityof 0.60-0.80 dL/g. It contains 100% poly(DL-lactide) that has ester endgroups. It is available from Lakeshore Biomaterials, Birmingham, Ala.

FIG. 7 is a graphic representation of clonidine HCl release for variousformulations (identified in Table 3) as measured by the cumulativeclonidine released percentage. In FIG. 7, the formulations contained: 10wt. % clonidine, the remainder 100 DL 7E (the inherent viscosity of the100 DL was 0.60-0.80 and had an ester end group) or 7 wt. % clonidine,the remainder 8515 DLG or 5 wt. % clonidine, the remainder 100 DL 7E(the inherent viscosity of the 100 DL was 0.60-0.80 and had an ester endgroup), or 10 wt. % clonidine, the remainder 100 DL 7E (the inherentviscosity of the 100 DL was 0.60-0.80 and had an ester end group) andthe pellets had small diameters of 0.5 mm. The clonidine formulationwith the 10% drug load had a faster release also because it had asmaller diameter, but increased surface area, which allowed a fasterdrug release. This formulation was dispersed better in the polymer asindicated by the fine mixing legend. The 10% clonidine formulation thatwas thicker in diameter and was less dispersed throughout the polymerhad a slower release profile. The lower drug load formulation of 7% hadthe longest release period of over 60 days. In general, increasing thedrug load was found to cause a more rapid release of the drug while thelower drug loads were found to produce a more sustained release effect.All formulations had an initial burst release within 1-2 days of between5% and 35% cumulative clonidine release.

FIG. 8 is a graphic representation of the cumulative in vitro releaseprofile for certain clonidine formulations having different processing.The depots had PLG polymer coatings (poly soln), solvent coating withethyl acetate (EtOAC), glacial acetic acid (glacial HoAc), or wasprocessed in a nitrogen environment and coated with ethyl acetate asindicated in the legend. The coatings can be applied by methods known inthe art (e.g., spray coating, dip coating, etc.). The solvents used tocoat the depot can be solvents known in the art, for example, acetone,methyl chloride, chloroform, EtOAC, etc. The coatings produced a releasefrom 12 to 35 days with the fastest release (over 100%) in theformulation that was placed in a nitrogen environment. The longestrelease was observed for the formulation with the polymer coating andhigh drug load of clonidine 7 wt. % where drug was released for over 35days.

FIG. 9 is a graphic representation of the cumulative release profilesfor certain irradiated clonidine HCl formulations produced as indicatedin Table 3. The slowest release was seen for clonidine formulations thatwere double extruded, where a first batch was mixed and then extrudedand then that batch was mixed again and extruded to form the doubleextruded composition. These formulations had a slower polymerdegradation and drug release at about day 30 when compared toformulations that were not double extruded. The formulations with theDLG 7E (the inherent viscosity of the 100 DL was 0.60-0.80 and had anester end group) polymer had a rapid release and a second burst aboutday 30.

FIG. 10 is a graphic representation of certain calculated daily releasemeasurements of clonidine from 2/3/4 pellet doses. The slowest releasewas seen for clonidine formulations that were double extruded, where afirst batch was mixed and then extruded and then that batch was mixedagain and extruded to form the double extruded depot. These formulationshad a slower polymer degradation and drug release at about day 30, whencompared to formulations that were not double extruded. The formulationswith the DLG 7E (the inherent viscosity of the 100 DL was 0.60-0.80 andhad an ester end group) polymer had a rapid release and a second burstabout day 30. All formulations had an initial burst release on day onefrom about 10 mcg-50 mcg and the daily release ranged from 0.5 mcg to 20mcg/day over about 48 days. The formulations that were not doubleextruded had a second initial burst at around day 25 to day 35 asindicated by the large peaks. These formulations did not have polymercoatings on the depot and, thus, had high initial bursts ranging from 30mcg-50 mcg.

FIG. 11 is a graphic representation of the calculated daily release ofclonidine from certain three pellet doses produced as indicated in Table3. Each pellet (drug depot) had an inner core of drug and polymer and anouter coating with varying degrees of thickness (a thick coating isabout 50-100 microns and a thin coating is about 5 microns to about ˜20microns). The thinnest coating (about 20 microns) had the highestinitial burst ranging from about 9-14 mcg, which was much less than theuncoated depots from FIG. 10. The formulations in FIG. 11 were designedto decrease the initial burst with the outer coating. In general, thethicker the coating on the polymer drug core, the slower the drugrelease from the depot.

FIG. 12 is a graphic representation of the cumulative in vitro releaseprofile of clonidine from certain coaxial formulations (Table 3). Theformulations containing clonidine loads having 7.76 wt. %, 6.92 wt. %,6.76 wt. %, or 8.0 wt. % had a polymer and drug core with no outercoating. In general, with respect to these 4 formulations, the higherthe drug loads, the faster the drug release and more release of the drugfrom the depot. For example, the drug depot having an 8.0 wt. % drugload (the highest load in the core group) released about 90 wt. % of thedrug from the depot at about 70 days. In the second group, theformulations containing clonidine loads having 12.1 wt. %, 7.6 wt. %,8.9 wt. % or 10.0 wt. % had a polymer and drug core with an outercoating to delay release. The higher the drug load, the thinner thecoating and the lower the drug load, the thicker the coating. Theseresults show that by varying the drug load, changing the polymer from DL7E (the inherent viscosity of the 100 DL was 0.60-0.80 and had an esterend group) to DL 5E (the inherent viscosity of the 100 DL was 0.45-0.55and had an ester end group) and changing the coating thickness (a thickcoating is about 50-100 microns and a thin coating would be 5 to about˜20 microns), the release profile of the drug depot was changed whereinthe higher drug loads (12.1 wt. % and 10 wt. %) had a higher %cumulative release and the lower drug loads (8.9 wt. % and 7.6 wt. %)had a lower % cumulative release.

FIG. 13 is a graphic representation of the cumulative in vitro releaseprofile for certain irradiated clonidine formulations in Table 3. Theformulations contained 5 wt. % clonidine drug loads and the drug depotwas either 1 mm or 0.8 mm. One formulation had a drug load of 7 wt. %.None of the formulations had a polymer coating. In general, the smallerthe diameter of the pellet, the more rapid release of the drug from thedrug depot as the smaller diameter pellets had increased surface areawhich can lead to a higher % cumulative release of drug from the drugdepot.

FIG. 14 is a graphic representation of the calculated daily release ofclonidine for certain three pellet dose formulations of FIG. 13 that didnot have coatings on them. All formulations had a high initial burstrelease on day one from about 28 mcg-32 mcg and daily release rangedfrom 0.5 mcg to 4 mcg/day over about 75-95 days. There was no coating onthese pellets, which lead to a high initial burst. All formulations hadconsistent release after the initial burst period.

FIG. 15 is a graphic representation of the cumulative release percentageof clonidine for certain formulations. The formulations containingclonidine loads having 3.54 wt. %, 7.38 wt. %, 5.0 wt. %, or 3.8 wt. %had polymer and drug core and polymer DL coating. The polymer for thedrug core was 100 DL 5E (the inherent viscosity of the 100 DL was0.45-0.55 and had an ester end group) and some had this polymer for thecoating (sheath) as indicated in the legend. Others had the drug corepolymer as DL 5E (the inherent viscosity of the DL was 0.45-0.55 and hadan ester end group) and the polymer coating (sheath) on the core asindicated in the legend was DL 7E (the inherent viscosity of the DL was0.60-0.80 and had an ester end group). The thinnest coating and highestdrug load (7.38 wt. % clonidine) had the fastest release and thickercoating and lowest drug load (3.54 wt. % clonidine) had the slower drugrelease considering both groups had the same polymer and coating 100 DL5E (a thick coating is about 50-100 microns and a thin coating would be5 to about ˜20 microns). The other group having 5.0 wt. % clonidine loadand 3.8 wt. % clonidine load had a polymer core of DL 5E and a polymercoating of DL 7E (sheath), which delayed drug release. The drug depotwith the higher drug load released the fastest. In general, the higherthe drug loads, the faster the drug release and more release of the drugfrom the depot, also the thicker the coating the slower the drugrelease.

FIG. 16 is a graphic representation of the micrograms of clonidinereleased for certain 3/4/5 pellet dose formulations of FIG. 15. Allformulations had either a 100 DL 5E coating on the core or a DL 7Ecoating on the core. All formulations had a lower initial burst effectas compared to uncoated pellets on day one, which was from about 3 mcg-5mcg and daily release ranged from 0.1 mcg to 5 mcg/day over about 55-92days. However, there was one formulation that had a high drug load of7.38 wt. % clonidine that had the fastest release over about 25 days anda peak release of about 13 mcg. This formulation may be useful where afast release is needed. All other formulations had consistent releaseafter the initial burst period with some having a release over 90 dayswith a release of from about 0.1 mcg/day to about 3 mcg/day.

FIG. 17 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 10 wt. % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 120 days, which is suitable for many chronicconditions.

FIG. 18 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 20 wt. % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 140 days, which is suitable for many chronicconditions.

FIG. 19 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 7.5 wt. % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 145 days, which is suitable for many chronicconditions.

FIG. 20 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 5 wt. % clonidine drug load and the polymer 100DL 7E had about 100 cumulative release % of drug released from the depotas long as 175 days, which is suitable for many chronic conditions.

FIG. 21 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 5 wt. % clonidine drug load, the polymer 8515DLG 7E and mPEG as a plasticizer had about 80 cumulative release % ofdrug released from the depot as long as 150 days, which is suitable formany chronic conditions.

FIG. 22 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 5 wt. % clonidine drug load and the polymer8515 DLG 7E had about 75 cumulative release % of drug released from thedepot as long as 135 days, which is suitable for many chronicconditions.

FIG. 23 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 50 to 75 cumulative release % of drugreleased from the depot as long as 160 days, which is suitable for manychronic conditions.

FIG. 24 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 90 cumulative release % of drug released fromthe depot for 7 days. The formulations were of a smaller size (0.75mm×0.75 mm), which increases the surface area for release as compared todepots with larger diameters.

FIG. 25 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had over 100 cumulative release % of drug released fromthe depot for over 30 days.

FIG. 26 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.Span 85 is a plasticizer for one formulation. All formulations had about30 to 50 cumulative release % of drug released from the depot for over50 days.

FIG. 27 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 5 wt. % clonidine drug load and the polymer 8515PLGA had about 100 cumulative release % of drug released from the depotas long as over 75 days, which is suitable for many chronic conditions.

FIG. 28 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 5 wt. % clonidine drug load and the polymer 8515PLGA and Span 65 as a plasticizer had about 65 cumulative release % ofdrug released from the depot as long as 70 days, which is suitable formany chronic conditions.

FIG. 29 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 90 to 110 cumulative release % of drugreleased from the depot for over 100 days, except one, which had about90 cumulative release % of drug released from the depot for about 20days.

FIG. 30 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 55 to 85 cumulative release % of drugreleased from the depot for over 28 days.

FIG. 31 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 10 wt. % clonidine drug load and the polymerDL-PLA had about 45 cumulative release % of drug released from the depotfor about 18 days, which may be suitable for acute conditions.

FIG. 32 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 2.All formulations had POE and 10% or 20% clonidine drug load. Allformulations had about 80 to 90 cumulative release % of drug releasedfrom the depot for over 120 days, except one formulation, which releaseddrug within about 35 days.

FIG. 33 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 2. Theformulation containing 10 wt. % clonidine drug load and the polymer POEhad about 100% cumulative release % of drug released from the depot forabout 100 days, which may be suitable for chronic conditions.

FIG. 34 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 2. Theformulation had about 35% cumulative release % of clonidine releasedfrom the depot for about 23 days.

Example 2

The inventors evaluated the efficacy of a five month Clonidine/PolymerDrug Depot in the Rat Chronic Constriction Injury Model. The animalmodel was the Bennett Model (Wistar rat). The purpose: To determinewhether a five month polymer clonidine-eluting depot can improve painassociated behavioral responses in a rat model of neuropathic pain.

Experimental Design: Four loose chromic gut ligatures, 1 mm apart, weretied around the common sciatic nerve at mid-thigh. Each animal receivedtreatment of a test or control article according to the dosing describedin Table 5.

TABLE 5 Group Number Treatment Dose Comments 1 Clonidine 0.02 mg/kg SCClonidine control 2 100 DL 7E 0% 4 pellets (3 mm × 0.7 mm) 3 100 DL 7E5% Clonidine HCl; 4 pellets (3 mm × 0.7 mm) 4 100 DL 5E 5% 3 pellets (3mm × 0.7 mm) 5 100 DL 5E 7% 3 pellets (3 mm × 0.7 mm) 6 100 DL 7E 7% 3pellets (3 mm × 0.7 mm) 7 POE 0% 5 pellets (1.5 mm × 0.7 mm) 8 POE 10and 20% clonidine-base; 5 pellets (1 20% @ 0.7 mm^(2;) 4 10% @ 1.5 mm ×0.7 mm)

The inventors have conducted the present study for a period of 64 daysand have employed the following two tests: (1) the Hargreaves test; and(2) the von Frey test. The Hargreaves Tests of Thermal Hyperalgesia wereconducted on days 7, 14, 21, 28, 35, 42, 49, 56 and 63. The von Freymonofilament test of mechanical allodynia (performed the day followingThermal testing) was conducted on days 8, 15, 22, 29, 36, 43, 50, 57 and64. The results of these tests are summarized in FIGS. 3 and 4 whichshow the efficacy of clonidine at the recited time periods.

The pain behavioral response (measured as a percentage of baseline) forthermal hyperalgesia (FIG. 3) indicates that clonidine deliveredsubcutaneously at 0.02 mg/kg/day consistently reduced the behavioralresponse when compared to either unloaded polymer depots (100 DL 7WControl or POE Control) (58% vs. 45%). All five clonidine-loaded polymerdepots were able to reduce pain behavioral responses when compared tounloaded depot; although, each formulation experienced a drop inefficacy at some point after the initial burst of drug at implantation.The pain behavioral response (measured as a percentage of baseline) formechanical allodynia indicates that clonidine delivered subcutaneouslyat 0.02 mg/kg/day reduced the behavioral response when compared toeither unloaded polymer depots (100 DL 7W Control or POE Control).

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. An implantable drug depot for reducing,preventing or treating dystonia and/or post-stroke spasticity in apatient in need of such treatment, the drug depot comprising at leastone biodegradeable polymer and clonidine or a pharmaceuticallyacceptable salt thereof in an amount from about 0.1 wt. % to about 30wt. % of the drug depot, wherein the drug depot is capable of releasingclonidine over a period of 5 to 135 days.
 2. An implantable drug depotaccording to claim 1, wherein said clonidine comprises from about 5 wt.% to about 15 wt. % of the drug depot.
 3. An implantable drug depotaccording to claim 1, wherein said clonidine is released in an amountbetween 0.005 and 1.0 mg per day for a period of 5 to 135 days.
 4. Animplantable drug depot according to claim 1, wherein said polymer iscapable of degrading in 200 days or less after said drug depot isadministered to reduce, prevent or treat dystonia and/or post-strokespasticity.
 5. An implantable drug depot according to claim 1, whereinthe at least one biodegradable polymer comprises one or more ofpoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof. 6.An implantable drug depot according to claim 1, wherein said clonidineis in the form of clonidine hydrochloride or a mixture of clonidine baseand a hydrochloride salt.
 7. An implantable drug depot according toclaim 1, wherein the drug depot releases: (i) a bolus dose of theclonidine; and (ii) an effective amount of the clonidine over a periodof at least fifty days.
 8. A method for treating dystonia and/orpost-stroke spasticity, wherein said method comprises implanting a drugdepot in an organism to reduce, prevent or treat dystonia and/orpost-stroke spasticity, wherein said drug depot comprises clonidine inan amount from about 0.1 wt. % to about 30 wt. % of the drug depot, andat least one biodegradable polymer.
 9. A method according to claim 8,wherein said clonidine comprises from about 5 wt. % to about 15 wt. % ofthe drug depot.
 10. A method according to claim 8, wherein saidbiodegradable polymer comprises at least 70 wt. % of the drug depot. 11.A method according to claim 8, wherein said clonidine is capable ofbeing released in an amount between 0.005 and 1.0 mg per day for aperiod of 5 to 135 days.
 12. A method according to claim 8, wherein thedrug depot is capable of releasing about 5% to about 100% of saidclonidine relative to a total amount of said clonidine loaded in thedrug depot over a period of 3 to 200 days after the drug depot isimplanted in said organism.
 13. A method according to claim 8, whereinsaid clonidine is in the form of clonidine hydrochloride or a mixture ofclonidine and a hydrochloride salt.
 14. An implantable drug depot usefulfor reducing, preventing or treating dystonia and/or post-strokespasticity in a patient in need of such treatment, the drug depotcomprising at least one biodegradeable polymer and a therapeuticallyeffective amount of clonidine, the drug depot being administered at asite to reduce, prevent or treat dystonia and/or post-stroke spasticity,wherein the drug depot is capable of releasing clonidine at an amountbetween 0.005 and 1.0 mg per day for a period of 5 to 135 days at thesite.
 15. An implantable drug depot according to claim 14, wherein saidpolymer is capable of degrading in 200 days or less after the drug depotis administered at the site.
 16. An implantable drug depot according toclaim 14, wherein said clonidine is released in an amount between 0.01and 0.1 mg per day for a period of 5 to 135 days at the site.
 17. Animplantable drug depot according to claim 14, wherein said clonidine ispresent in an amount of about 0.1 to about 30 wt. % of the drug depotand said polymer is present in an amount of about 70 to about 99.9 wt. %of the drug depot.
 18. A sustain release composition comprising aneffective amount of clonidine or a pharmaceutically acceptable saltthereof in an implantable drug depot, wherein said clonidine or apharmaceutically acceptable salt thereof is present in an amount torelieve post-stroke spasticity and/or dystonia for a period of 5 to 135days and wherein said implantable drug depot facilitates sustain releaseof clonidine over said period.
 19. A method of making an implantabledrug depot of claim 1, the method comprising combining a biocompatiblepolymer and a therapeutically effective amount of clonidine or apharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.